Med25 is required for estrogen receptor alpha (ERα)-mediated regulation of human CYP2C9 expression

The CYP2C subfamily of cytochrome P450 enzymes is an important class of drug metabolizing enzymes in human liver. CYP2C9 is the most abundant member of the human CYP2C subfamily in liver and metabolizes similar to 15% of the therapeutic drugs as well as other xenobiotics and endogenous compounds. A number of nuclear receptors including xenobiotic-sensing receptors such as the constitutive androstane receptor (CAR), pregnane X receptor (PXR), and glucocorticoid receptor (GR) as well as liver enriched receptors hepatic nuclear factor 4 alpha (HNF4 alpha) and the estrogen receptor alpha (ER alpha) regulate CYP2C9 expression. Here, we show that Med25, a variable component of Mediator complex, enhanced ligand dependent ER alpha-mediated transcriptional activation of CYP2C9 promoter and interacts with activated ERa by 17 beta-estradiol through its C-terminal LXXLL motif. In conclusion, Med25 is identified as a new coactivator of ER alpha that is required for ERa-mediated regulation of CYP2C9 expression. (C) 2014 Elsevier Inc. All rights reserved.